Implication for health policy/practice/research/medical education: The current literature indicates that maintaining adequate vitamin D levels may be an important consideration in the treatment of hypertension, especially in individuals with vitamin D insufficiency and deficiency

Ajabshir, Sahar

Asif, Arif

Nayer, Ali

Journal of Nephropathology

PubMed

DigitalCommons@Florida International University

Florida International UniversityFIU Digital CommonsDepartment of Dietetics and Nutrition Robert Stempel College of Public Health & SocialWork4-1-2014The Effects of Vitamin D on the Renin-AngiotensinSystemSahar AjabshirDepartment of Dietetics and Nutrition, Florida International University, sajab001@fiu.eduArif AsifAlbany Medical CollegeAli NayerUniversity of MiamiFollow this and additional works at: http://digitalcommons.fiu.edu/dietetics_nutrition_facPart of the Dietetics and Clinical Nutrition CommonsThis work is brought to you for free and open access by the Robert Stempel College of Public Health & Social Work at FIU Digital Commons. It hasbeen accepted for inclusion in Department of Dietetics and Nutrition by an authorized administrator of FIU Digital Commons. For more information,please contact dcc@fiu.edu.Recommended CitationAjabshir S, Asif A, Nayer A. The effects of vitamin D on the renin-angiotensin system. J Nephropathol. 2014; 3(2): 41-43. DOI:10.12860/jnp.2014.09www.nephropathol.com                       DOI: 10.12860/jnp.2014.09               J Nephropathol. 2014; 3(2): 41-43Journal of  Nephropathology *Corresponding author: Ali Nayer, Division of  Nephrology and Hypertension, University of  Miami, Clinical Research Building, suite 825, 1120 NW 14th St., Miami, FL 33136, USA. Tel: 305.243.3583, fax: 305.243.3506, E-mail: anayer@med.miami.edu1Department of  Dietetics and Nutrition, Florida International University, Miami, USA2Division of  Nephrology and Hypertension, Albany Medical College, Albany, USA3Division of  Nephrology and Hypertension, University of  Miami, Miami, USASahar Ajabshir1, Arif  Asif2, Ali Nayer3,*ARTICLE INFOArticle type:EditorialArticle history:Received: 15 December 2013Accepted: 25 December 2013Published online: 1 April 2014DOI: 10.12860/jnp.2014.09Keywords:Vitmain DRenin-angiotensin systemBlood pressureHypertensionImplication for health policy/practice/research/medical education:The current literature indicates that maintaining adequate vitamin D levels may be an important consideration in the treatment of  hypertension, especially in individuals with vitamin D insufficiency and deficiency.Please cite this paper as: Ajabshir S, Asif  A, Nayer A. The effects of  vitamin D on the renin-an-giotensin system. J Nephropathol. 2014; 3(2): 41-43.  DOI: 10.12860/jnp.2014.09EditorialThe effects of  vitamin D on the renin-angiotensin system In humans, 80-90% of  required vitamin D is made in the skin upon sun exposure and the remaining 10-20% is ingested in fish, eggs and fortified dairy products. In the liver, vitamins D2(ergocalciferol) and D3(cholecalcif-erol) are converted into 25-hydroxyvitamin D2 (25[OH]D2) and 25-hydroxyvitamin D3 (25(OH]D3), respectively (1). In the kidney, 25(OH)D is converted to its biologically active form 1,25-di-hydroxyvitamin D (1,25[OH]2D) by 1α-hydrox-ylase. The serum level of  25(OH)D is used to determine vitamin D status and normally ranges between 30-100 ng/mL (75–250 nmol/L).  Vi-tamin D insufficiency and deficiency are defined as serum 25(OH)D levels of  20-30 mg/dL (50-75 nmol/L) and <20 ng/mL (50 nmol/L), re-spectively (2).  The critical role of  1,25(OH)2D in calcium and phosphorus homeostasis is well established (1,2).  Accumulating evidence indi-cates that vitamin D also plays an important role in regulating the blood pressure. A recent randomized, double-blind, placebo con-trolled study conducted by Nasri et al. demonstrat-ed that oral supplementation of  vitamin D led to a decrease in the blood pressure in individuals with diabetes mellitus (3).  Sixty individuals were ran-domized to receive either vitamin D3 50,000 IU per week (n=30) or placebo (n=30) for 12 weeks. Five individuals (8.3%) had vitamin D deficiency and 27 others (45%) had vitamin D insufficien-cy.  Vitamin D supplementation increased serum 25(OH)D levels from 84±52 nmol/L to 164±57 nmol/L (P= 0.001). Vitamin D supplementa-tion led to a decrease in both systolic (121±13 to 110±9 mm Hg; P= 0.001) and diastolic blood pressure (81±8 to 76±7 mm Hg, P= 0.046). No statistically significant change in blood pressure was observed in the placebo group.The pivotal role of  the renin-angiotensin system in the regulation of  the blood pressure is well established (Figure 1). Renin is secreted by the juxtaglomerular cells of  the kidney in response Journal of  Nephropathology, Vol 3 No 2, April 2014        www.nephropathol.com42to decreased renal blood flow. It converts plas-ma angiotensinogen to angiotensin I, which is then converted to angiotensin II by angioten-sin-converting enzyme. Angiotensin II leads to increased water and sodium reabsorption in the kidney and vasoconstriction.  Mounting evi-dence indicates that vitamin D regulates the re-nin-angiotensin system. An inverse relationship between the blood pressure and serum 25(OH)D levels has been documented in a number of the epidemiological studies (4,5).  In a cross-sec-tional study, Forman et al. explored the relation between 25(OH)D and the renin-angiotensin sys-tem in 184 individuals with normal blood pres-sure (6).  Compared with vitamin D-sufficient individuals, those with vitamin D deficiency and insufficiency had greater plasma angiotensin II levels and a trend for higher plasma renin activity. In addition, the activity of  the renin-angiotensin system in the kidney, as measured by the renal plasma flow in response to angiotensin II infu-sion, was greater in vitamin D-deficient than in Ajabshir S et al.vitamin D-sufficient individuals.  These results suggested that decreased plasma 25(OH)D levels were associated with increased activity of  the re-nin angiotensin system.  Resnick et al. investigat-ed the relation between the plasma renin activity and calcium-regulating hormones including calci-tonin, 1,25(OH)2D3 and parathyroid hormone in 51 individuals with essential hypertension (7).  An inverse relation of  the serum 1,25(OH)2D3 level to the plasma renin activity (r= −0.65, P< 0.001) was observed. This study corroborated a link be-tween calcium homeostasis, vitamin D metabo-lism and the renin-angiotensin system.To unravel the molecular mechanisms involved in vitamin D-mediated regulation of  the renin-an-giotensin system, mice with loss-of-function mu-tations involving vitamin D receptor gene (VDR-null mice) were examined.  The VDR-null mice develop hypocalcemia at 3 weeks of  age, hyper-parathyroidism, rickets and osteomalacia (8).  Li et al. demonstrated that renin gene expression in the kidney and angiotensin II levels in the plasma were substantially increased in the VDR-null mice leading to hypertension and cardiac hypertrophy (9).  In wild-type mice, pharmacological inhibi-tion of  1,25(OH)2D3 synthesis led to an increase in renin gene expression, whereas 1,25(OH)2D3 treatment suppressed renin expression. Similar-ly, 1,25(OH)2D3 markedly suppressed renin gene expression in cultured cells by a VDR-mediated mechanism. These investigators also demonstrat-ed that the effect of  vitamin D on renin gene expression was independent of  calcium metab-olism. The authors concluded that 1,25(OH)2D3 is a negative regulator of  the renin-angioten-sin system. Subsequently, it was shown that 1,25(OH)2D3 suppressed renin gene expression by binding to the transcription factor cAMP re-sponse element-binding protein (CREB), thereby suppressing the activity of  the cAMP response element in the renin gene promoter (10).To determine whether the inhibitory effects of 1,25(OH)2D on the renin-angiotensin system is dependent on calcium or phosphorous, Zhou el al. examined the effects of  dietary interventions Figure 1. The effects of  vitamin D on the renin-angio-tensin system. 1,25-dihydroxyvitamin D suppresses renin gene expression, thereby inhibiting the renin-angiotensin system. ACE, angiotensin-converting enzyme; H2O, water; Na, sodium. www.nephropathol.com      Journal of  Nephropathology, Vol 3, No 2, April 2014 43Vitamin D  and renin-angiotensin systemin 1α-hydroxylase knockout mice. Phenotypical-ly resembling VDR-null mice, 1α-hydroxylase knockout mice demonstrate undetectable serum 1,25(OH)2D levels and develop hypocalcemia, hypophosphatemia, secondary hyperparathy-roidism, growth retardation and skeletal abnor-malities characteristic of  rickets (11). Zhou et al. demonstrated that 1α-hydroxylase knockout mice developed hypertension and cardiac hypertrophy associated with the activation of  the renin-an-giotensin system in the kidney and heart (12). Despite the normalization of  the serum calcium and phosphorus levels, a calcium- and phospho-rus-fortified diet neither normalized  the blood pressure nor suppressed the activity of  the re-nin-angiotensin system in the 1α-hydroxylase knockout mice.  However, 1,25(OH)2D treat-ment led to the normalization of  the activity of the renin-angiotensin system and blood pressure.In summary, the current literature indicates that maintaining adequate vitamin D levels may be an important consideration in the treatment of  hy-pertension, especially in individuals with vitamin D insufficiency and deficiency.Authors’ contributionsAll authors wrote the paper equally.Conflict of  interestsAuthors declare no conflicts of  interest.Funding/SupportThis work received no funding from public, com-mercial or not-for-profit organizations.References1. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005; 289(1): F8-28.2. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-81.3. Nasri H, Behradmanesh S, Ahmadi A, Rafieian-Kopaei M. Impact of  oral vitamin D (cholecalciferol) replacement therapy on blood pressure in type 2 diabetes patients; a randomized, double-blind, placebo controlled clinical trial. J Nephropathol 2014; 3(1):29-33.4. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens 2007; 20(7):713-9.5. Hintzpeter B, Mensink GB, Thierfelder W, Müller MJ, Scheidt-Nave C. Vitamin D status and health correlates among German adults. Eur J Clin Nutr 2008; 62(9): 1079-89. 6. Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of  the renin-angiotensin systemin humans. Hypertension 2010; 55(5):1283-8. 7. Resnick LM, Müller FB, Laragh JH. Calcium-regulating hormones in essential hypertension. Relation to plasma renin activity and sodium metabolism. Ann Intern Med 1986; 105(5):649-54.8. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, et al. Targeted ablation of  the vitamin D receptor: an animal model of  vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci U S A 1997; 94(18):9831-5. 9. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of  the renin-angiotensin system. J Clin Invest 2002; 110(2):229-38.10. Yuan W, Pan W, Kong J, Zheng W, Szeto FL, Wong KE, et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of  the cyclic AMP response element in the renin gene promoter. J Biol Chem 2007; 282(41): 29821-30. 11. Panda DK, Miao D, Tremblay ML, Sirois J, Farookhi R, Hendy GN, et al. Targeted ablation of  the 25-hydroxyvitamin D 1alpha -hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc Natl Acad Sci U S A 2001; 98(13): 7498-503. 12. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of  the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int 2008; 74(2): 170-9.Copyright © 2014 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of  the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The Effects of Vitamin D on the Renin-Angiotensin System

Implication for health policy/practice/research/medical education
:
The current literature indicates that maintaining adequate vitamin D levels may be an important
consideration in the treatment of hypertension, especially in individuals with vitamin D insufficiency
and deficiency

Ajabshir, Sahar

Asif, Arif

Nayer, Ali

University of Miami: Scholarship Miami

The effects of vitamin D on the renin-angiotensin system

Sahar Ajabshir

Arif Asif

Ali Nayer

Directory of Open Access Journals

www.nephropathol.com                       DOI: 10.12860/jnp.2014.09               J Nephropathol. 2014; 3(2): 41-43Journal of  Nephropathology *Corresponding author: Ali Nayer, Division of  Nephrology and Hypertension, University of  Miami, Clinical Research Building, suite 825, 1120 NW 14th St., Miami, FL 33136, USA. Tel: 305.243.3583, fax: 305.243.3506, E-mail: anayer@med.miami.edu1Department of  Dietetics and Nutrition, Florida International University, Miami, USA2Division of  Nephrology and Hypertension, Albany Medical College, Albany, USA3Division of  Nephrology and Hypertension, University of  Miami, Miami, USASahar Ajabshir1, Arif  Asif2, Ali Nayer3,*ARTICLE INFOArticle type:EditorialArticle history:Received: 15 December 2013Accepted: 25 December 2013Published online: 1 April 2014DOI: 10.12860/jnp.2014.09Keywords:Vitmain DRenin-angiotensin systemBlood pressureHypertensionImplication for health policy/practice/research/medical education:The current literature indicates that maintaining adequate vitamin D levels may be an important consideration in the treatment of  hypertension, especially in individuals with vitamin D insufficiency and deficiency.Please cite this paper as: Ajabshir S, Asif  A, Nayer A. The effects of  vitamin D on the renin-an-giotensin system. J Nephropathol. 2014; 3(2): 41-43.  DOI: 10.12860/jnp.2014.09EditorialThe effects of  vitamin D on the renin-angiotensin system In humans, 80-90% of  required vitamin D is made in the skin upon sun exposure and the remaining 10-20% is ingested in fish, eggs and fortified dairy products. In the liver, vitamins D2(ergocalciferol) and D3(cholecalcif-erol) are converted into 25-hydroxyvitamin D2 (25[OH]D2) and 25-hydroxyvitamin D3 (25(OH]D3), respectively (1). In the kidney, 25(OH)D is converted to its biologically active form 1,25-di-hydroxyvitamin D (1,25[OH]2D) by 1α-hydrox-ylase. The serum level of  25(OH)D is used to determine vitamin D status and normally ranges between 30-100 ng/mL (75–250 nmol/L).  Vi-tamin D insufficiency and deficiency are defined as serum 25(OH)D levels of  20-30 mg/dL (50-75 nmol/L) and <20 ng/mL (50 nmol/L), re-spectively (2).  The critical role of  1,25(OH)2D in calcium and phosphorus homeostasis is well established (1,2).  Accumulating evidence indi-cates that vitamin D also plays an important role in regulating the blood pressure. A recent randomized, double-blind, placebo con-trolled study conducted by Nasri et al. demonstrat-ed that oral supplementation of  vitamin D led to a decrease in the blood pressure in individuals with diabetes mellitus (3).  Sixty individuals were ran-domized to receive either vitamin D3 50,000 IU per week (n=30) or placebo (n=30) for 12 weeks. Five individuals (8.3%) had vitamin D deficiency and 27 others (45%) had vitamin D insufficien-cy.  Vitamin D supplementation increased serum 25(OH)D levels from 84±52 nmol/L to 164±57 nmol/L (P= 0.001). Vitamin D supplementa-tion led to a decrease in both systolic (121±13 to 110±9 mm Hg; P= 0.001) and diastolic blood pressure (81±8 to 76±7 mm Hg, P= 0.046). No statistically significant change in blood pressure was observed in the placebo group.The pivotal role of  the renin-angiotensin system in the regulation of  the blood pressure is well established (Figure 1). Renin is secreted by the juxtaglomerular cells of  the kidney in response Journal of  Nephropathology, Vol 3 No 2, April 2014        www.nephropathol.com42to decreased renal blood flow. It converts plas-ma angiotensinogen to angiotensin I, which is then converted to angiotensin II by angioten-sin-converting enzyme. Angiotensin II leads to increased water and sodium reabsorption in the kidney and vasoconstriction.  Mounting evi-dence indicates that vitamin D regulates the re-nin-angiotensin system. An inverse relationship between the blood pressure and serum 25(OH)D levels has been documented in a number of the epidemiological studies (4,5).  In a cross-sec-tional study, Forman et al. explored the relation between 25(OH)D and the renin-angiotensin sys-tem in 184 individuals with normal blood pres-sure (6).  Compared with vitamin D-sufficient individuals, those with vitamin D deficiency and insufficiency had greater plasma angiotensin II levels and a trend for higher plasma renin activity. In addition, the activity of  the renin-angiotensin system in the kidney, as measured by the renal plasma flow in response to angiotensin II infu-sion, was greater in vitamin D-deficient than in Ajabshir S et al.vitamin D-sufficient individuals.  These results suggested that decreased plasma 25(OH)D levels were associated with increased activity of  the re-nin angiotensin system.  Resnick et al. investigat-ed the relation between the plasma renin activity and calcium-regulating hormones including calci-tonin, 1,25(OH)2D3 and parathyroid hormone in 51 individuals with essential hypertension (7).  An inverse relation of  the serum 1,25(OH)2D3 level to the plasma renin activity (r= −0.65, P< 0.001) was observed. This study corroborated a link be-tween calcium homeostasis, vitamin D metabo-lism and the renin-angiotensin system.To unravel the molecular mechanisms involved in vitamin D-mediated regulation of  the renin-an-giotensin system, mice with loss-of-function mu-tations involving vitamin D receptor gene (VDR-null mice) were examined.  The VDR-null mice develop hypocalcemia at 3 weeks of  age, hyper-parathyroidism, rickets and osteomalacia (8).  Li et al. demonstrated that renin gene expression in the kidney and angiotensin II levels in the plasma were substantially increased in the VDR-null mice leading to hypertension and cardiac hypertrophy (9).  In wild-type mice, pharmacological inhibi-tion of  1,25(OH)2D3 synthesis led to an increase in renin gene expression, whereas 1,25(OH)2D3 treatment suppressed renin expression. Similar-ly, 1,25(OH)2D3 markedly suppressed renin gene expression in cultured cells by a VDR-mediated mechanism. These investigators also demonstrat-ed that the effect of  vitamin D on renin gene expression was independent of  calcium metab-olism. The authors concluded that 1,25(OH)2D3 is a negative regulator of  the renin-angioten-sin system. Subsequently, it was shown that 1,25(OH)2D3 suppressed renin gene expression by binding to the transcription factor cAMP re-sponse element-binding protein (CREB), thereby suppressing the activity of  the cAMP response element in the renin gene promoter (10).To determine whether the inhibitory effects of 1,25(OH)2D on the renin-angiotensin system is dependent on calcium or phosphorous, Zhou el al. examined the effects of  dietary interventions Figure 1. The effects of  vitamin D on the renin-angio-tensin system. 1,25-dihydroxyvitamin D suppresses renin gene expression, thereby inhibiting the renin-angiotensin system. ACE, angiotensin-converting enzyme; H2O, water; Na, sodium. www.nephropathol.com      Journal of  Nephropathology, Vol 3, No 2, April 2014 43Vitamin D  and renin-angiotensin systemin 1α-hydroxylase knockout mice. Phenotypical-ly resembling VDR-null mice, 1α-hydroxylase knockout mice demonstrate undetectable serum 1,25(OH)2D levels and develop hypocalcemia, hypophosphatemia, secondary hyperparathy-roidism, growth retardation and skeletal abnor-malities characteristic of  rickets (11). Zhou et al. demonstrated that 1α-hydroxylase knockout mice developed hypertension and cardiac hypertrophy associated with the activation of  the renin-an-giotensin system in the kidney and heart (12). Despite the normalization of  the serum calcium and phosphorus levels, a calcium- and phospho-rus-fortified diet neither normalized  the blood pressure nor suppressed the activity of  the re-nin-angiotensin system in the 1α-hydroxylase knockout mice.  However, 1,25(OH)2D treat-ment led to the normalization of  the activity of the renin-angiotensin system and blood pressure.In summary, the current literature indicates that maintaining adequate vitamin D levels may be an important consideration in the treatment of  hy-pertension, especially in individuals with vitamin D insufficiency and deficiency.Authors’ contributionsAll authors wrote the paper equally.Conflict of  interestsAuthors declare no conflicts of  interest.Funding/SupportThis work received no funding from public, com-mercial or not-for-profit organizations.References1. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005; 289(1): F8-28.2. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-81.3. Nasri H, Behradmanesh S, Ahmadi A, Rafieian-Kopaei M. Impact of  oral vitamin D (cholecalciferol) replacement therapy on blood pressure in type 2 diabetes patients; a randomized, double-blind, placebo controlled clinical trial. J Nephropathol 2014; 3(1):29-33.4. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens 2007; 20(7):713-9.5. Hintzpeter B, Mensink GB, Thierfelder W, Müller MJ, Scheidt-Nave C. Vitamin D status and health correlates among German adults. Eur J Clin Nutr 2008; 62(9): 1079-89. 6. Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of  the renin-angiotensin systemin humans. Hypertension 2010; 55(5):1283-8. 7. Resnick LM, Müller FB, Laragh JH. Calcium-regulating hormones in essential hypertension. Relation to plasma renin activity and sodium metabolism. Ann Intern Med 1986; 105(5):649-54.8. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, et al. Targeted ablation of  the vitamin D receptor: an animal model of  vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci U S A 1997; 94(18):9831-5. 9. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of  the renin-angiotensin system. J Clin Invest 2002; 110(2):229-38.10. Yuan W, Pan W, Kong J, Zheng W, Szeto FL, Wong KE, et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of  the cyclic AMP response element in the renin gene promoter. J Biol Chem 2007; 282(41): 29821-30. 11. Panda DK, Miao D, Tremblay ML, Sirois J, Farookhi R, Hendy GN, et al. Targeted ablation of  the 25-hydroxyvitamin D 1alpha -hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc Natl Acad Sci U S A 2001; 98(13): 7498-503. 12. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of  the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int 2008; 74(2): 170-9.Copyright © 2014 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of  the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The Effects of Vitamin D on the Renin-Angiotensin System

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